The overall objective of this research is to describe the relationship of DNA metabolism and the process of aging. In particular, we wish to evaluate the possible deterioration of DNA function as a precedent or concomitant of the aging process and whether such an evaluation is consistent with somatic mutation as the underlying mechanism of aging. We will measure several indicators of DNA function in cultured cells with relevance to aging: (1) patterns of DNA strand break rejoining in gamma-irradiated cells; (2) patterns of removal of sites sensitive to exogenous endonucleases; (3) cellular mediation of chromatin rearrangements; and (4) intrinsically induced sister-chromatid-exchanges. We will examine these endpoints in aneuploid lines and diploid strains derived from mammals of different life spans. We will measure these endpoints in detail in two major systems: human diploid fibroblasts and embryonic Syrian hamster cells. The former system will permit comparisons with other laboratories and the latter offers greater experimental latitude in that we have developed techniques for the control of senescence in these cultures. We will develop this rapidly and reproducibly senescing system as a major tool for the study of in vitro senescence. We will begin development of techniques for the measurement of DNA metabolism in vivo in aging animals. We will continue our studies of DNA metabolic properties of human mutant (variant cells which have aberrant DNA metabolism and which may have special relevance to aging: Progeria, Xeroderma pigmentosum, Ataxia telangiectasia, Fanconi's anemia and deletion type retinoblastoma.